Supplementary Figures, Table and Movie Legend from Blood Vessel Maturation and Response to Vascular-Disrupting Therapy in Single Vascular Endothelial Growth Factor-A Isoform–Producing Tumors
Supplementary Figures, Table and Movie Legend from Blood Vessel Maturation and Response to Vascular-Disrupting Therapy in Single Vascular Endothelial Growth Factor-A Isoform–Producing Tumors
Supplementary Figure 3 from Blood Vessel Maturation and Response to Vascular-Disrupting Therapy in Single Vascular Endothelial Growth Factor-A Isoform–Producing Tumors
Evaluation of: Shukla R, Kanna VK, Vinod P, Sankhwar ML, Yadav RS: Platelet dopamine: D2-receptor binding in patients with migraine. Cephalalgia DOI: 10.1111/j.1468-2982.2008.01760.X (2009) (Epub ahead of print). This study aimed to measure the level of platelet dopamine binding to the dopamine D2 receptor in migraineurs, using 3H-spiperone as a radioligand, and compared samples with control subjects. Patients adhering to the International Headache Society classification of migraine were shown to have significantly reduced dissociation constant (Kd: 1.71 ± 0.19 nM) for D2-receptor binding compared with controls. There was no relationship between Kd and other specific clinical features, such as migraine type, frequency and vomiting. The findings point to a relationship between dopamine binding and migraine, however further studies with larger patient groups are necessary to evaluate the exact role of dopamine and specific clinical features.
Animal models of human disease have been extremely helpful both in advancing the understanding of brain disorders and in developing new therapeutic approaches. Models for studying headache mechanisms, particularly those directed at migraine, have been developed and exploited efficiently in the last decade, leading to better understanding of the potential mechanisms of the disorder and of the action for antimigraine treatments. Model systems employed have focused on the pain-producing cranial structures, the large vessels and dura mater, in order to provide reproducible physiological measures that could be subject to pharmacological exploration. A wide range of methods using both in vivo and in vitro approaches are now employed; these range from manipulation of the mouse genome in order to produce animals with human disease-producing mutations, through sensitive immunohistochemical methods to vascular, neurovascular and electrophysiological studies. No one model system in experimental animals can explain all the features of migraine; however, the systems available have begun to offer ways to dissect migraine's component parts to allow a better understanding of the problem and the development of new treatment strategies.
The purpose of the study was to develop a mouse model to study trigeminovascular mechanisms using intravital microscopy on a closed cranial window. In addition, we studied exogenous and endogenous calcitonin gene-related peptide (CGRP)-mediated vasodilation in dural arteries. Arteries in C57BL/6Jico mice were constricted with endothelin-1, which reduced the baseline diameter by 65-75%. Subsequently, vasodilation was induced by α-CGRP, capsaicin or transcranial electrical stimulation of perivascular trigeminal nerves in the absence or presence of different concentrations of BIBN4096BS or sumatriptan. Both α-CGRP and capsaicin induced vasodilation in preconstricted arteries. Transcranial electrical stimulation also induced current-dependent relaxation of dural arteries with 100 μA producing maximal dilation in the control group. BIBN4096BS blocked the responses evoked by ä-CGRP and capsaicin, as well as electrical stimulation, whereas sumatriptan attenuated only vasodilation induced by electrical stimulation. This model is likely to prove useful in dissecting elements of the trigeminovascular system and for exploring pathophysiological aspects of migraine, especially in future studies using transgenic mice with mutations relevant to those observed in patients with migraine.
A missense mutation of the CACNA1A gene that encodes the α 1A subunit of the voltage‐dependent P/Q‐type calcium channel has been discovered in patients suffering from familial hemiplegic migraine. This suggested that calcium channelopathies may be involved in migraine more broadly, and established the importance of genetic mechanisms in migraine. Channelopathies share many clinical characteristics with migraine, and thus exploring calcium channel functions in the trigeminovascular system may give insights into migraine pathophysiology. It is also known that drugs blocking the P/Q‐ and N‐type calcium channels have been successful in other animal models of trigeminovascular activation and head pain. In the present study, we used intravital microscopy to examine the effects of specific calcium channel blockers on neurogenic dural vasodilatation and calcitonin gene‐related peptide (CGRP)‐induced dilation. The L‐type voltage‐dependent calcium channel blocker calciseptine significantly attenuated (20 μ g kg −1 , n =7) the dilation brought about by electrical stimulation, but did not effect CGRP‐induced dural dilation. The P/Q‐type voltage‐dependent calcium channel blocker ω ‐agatoxin‐IVA (20 μ g kg −1 , n =7) significantly attenuated the dilation brought about by electrical stimulation, but did not effect CGRP‐induced dural dilation. The N‐type voltage‐dependent calcium channel blocker ω ‐conotoxin‐GVIA (20 μ g kg −1 , n =8 and 40 μ g kg −1 , n =7) significantly attenuated the dilation brought about by electrical stimulation, but did not effect CGRP‐induced dural dilation. It is thought that the P/Q‐, N‐ and L‐type calcium channels all exist presynaptically on trigeminovascular neurons, and blockade of these channels prevents CGRP release, and, therefore, dural blood vessel dilation. These data suggest that the P/Q‐, N‐ and L‐type calcium channels may be involved in trigeminovascular nociception. British Journal of Pharmacology (2003) 140 , 558–566. doi: 10.1038/sj.bjp.0705456
Calcitonin gene‐related peptide (CGRP) is released into the cranial circulation of humans during acute migraine. To determine whether CGRP is involved in neurotransmission in craniovascular nociceptive pathways, we microiontophoresed onto neurons in the trigeminocervical complex and intravenously administered the CGRP receptor antagonists α ‐CGRP‐(8–37) and BIBN4096BS. Cats were anaesthetised with α ‐chloralose, and using halothane during surgical preparation. A craniotomy and C 1 /C 2 laminectomy allowed access to the superior sagittal sinus (SSS) and recording site. Recordings of activity in the trigeminocervical complex evoked by electrical stimulation of the SSS were made. Multibarrelled micropipettes incorporating a recording electrode were used for microiontophoresis of test substances. Cells recorded received wide dynamic range (WDR) or nociceptive specific (NS) input from cutaneous receptive fields on the face or forepaws. Cell firing was increased to 25–30 Hz by microiontophoresis of L ‐glutamate ( n =43 cells). Microiontophoresis of α ‐CGRP excited seven of 17 tested neurons. BIBN4096BS inhibited the majority of units (26 of 38 cells) activated by L ‐glutamate, demonstrating a non‐presynaptic site of action for CGRP. α ‐CGRP‐(8–37) inhibited a similar proportion of units (five of nine cells). Intravenous BIBN4096BS resulted in a dose‐dependent inhibition of trigeminocervical SSS‐evoked activity (ED 50 31 μ g kg –1 ). The maximal effect observed within 30 min of administration. The data suggest that there are non‐presynaptic CGRP receptors in the trigeminocervical complex that can be inhibited by CGRP receptor blockade and that a CGRP receptor antagonist would be effective in the acute treatment of migraine and cluster headache. British Journal of Pharmacology (2004) 142 , 1171–1181. doi: 10.1038/sj.bjp.0705807
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